Disease relevance of PDR1

• These data underscore the role of the pleiotropic drug resistance network in regulating camptothecin toxicity and are consistent with a model of decreased intracellular concentrations of camptothecin resulting from the increased expression of the SNQ2 transporter [1].
• Here we show that disruption of C. glabrata PDR1 conferred equivalent fluconazole hypersensitivity (MIC = 2 microg ml(-1)) to both F15 and 66032 and eliminated both constitutive and fluconazole-induced CDR1-PDH1 expression [2].
• Mutations in the human ANT1 gene, coding for the ADP/ATP carrier, are responsible for the autosomal dominant and recessive forms of progressive external ophthalmoplegia, mitochondrial disorders characterized by the presence of multiple deletions of mitochondrial DNA in affected tissues [3].

High impact information on PDR1

• Targeting of Ant1p to peroxisomes was dependent on Pex3p and Pex19p, two peroxins specifically required for peroxisomal membrane protein insertion [4].
• Ant1p was found to be an integral protein of the peroxisomal membrane and expression of ANT1 was oleic acid inducible [4].
• This and the observed repression of apoptosis by the ANT-1-interacting protein cyclophilin D suggest that the suicidal effect of ANT-1 is mediated by specific protein-protein interactions within the permeability transition pore [5].
• We discovered a nuclear import pathway mediated by the product of the previously identified Saccharomyces cerevisiae gene PDR6 (pleiotropic drug resistance) [6].
• Complementation cloning and linkage analysis led to the identification of the dominant mutation TPE1-1 as a new allele of PDR1 and the semidominant mutation tpe2-1 as a new allele of PDR3 [7].

Chemical compound and disease context of PDR1

• Our results suggest that Cin5 and Ydr259c might be involved in pleiotropic drug-resistance and might protect yeast against the toxicity of cisplatin and other alkylating agents via a single mechanism [8].

Biological context of PDR1

• Pdr13p requires the presence of both the PDR1 structural gene and the Pdr1p binding sites in target promoters to mediate its effect on drug resistance and gene expression [9].
• Here we report SCT1 is allelic to PDR1 and that a Thr-879 to Met substitution in the PDR1-101 transcription factor confers multiple drug resistance [1].
• The resistant phenotype in these groups was found to be caused by allelic forms of the genes AFG2, PDR1, and PDR3 [10].
• In this study, we identified four genes on chromosome II that affect the steady-state level of PDR5 transcript in addition to a previously identified positive regulator, PDR1 [11].
• The nucleotide sequences of 13 alleles of PDR1, comprising 6 multidrug resistance mutants, 1 intragenic suppressor and 6 wild types, have been determined [12].

Anatomical context of PDR1

• Concomitantly, the level of PDR5 mRNA, of Pdr5p protein, and of its associated nucleoside triphosphatase activity, was strongly increased in the plasma membranes of the PDR1 mutants [12].
• Multiple signals from dysfunctional mitochondria activate the pleiotropic drug resistance pathway in Saccharomyces cerevisiae [13].
• The transcription regulators, PDR1 and PDR3, have been shown to activate the transcription of numerous genes involved in a wide range of functions, including resistance to physical and chemical stress, membrane transport, and organelle function in Saccharomyces cerevisiae [7].
• These data suggest that Pdr1p and Pdr3p may act to modulate the lipid composition of membranes in S. cerevisiae through activation of sphingolipid biosynthesis along with other target genes [14].
• No Delta pH was present in ant1 Delta cells, indicating that the peroxisomal pH is regulated in an ATP-dependent way and suggesting that Ant1p activity is directly involved in maintenance of the peroxisomal pH [15].

Associations of PDR1 with chemical compounds

• Our data demonstrate that Pdr5 and Snq2 can transport steroid substrates in vivo and suggest that steroids and/or related membrane lipids could represent physiological substrates for certain yeast ABC transporters, which are otherwise involved in the development of pleiotropic drug resistance [16].
• We show here that a pdr1-3 mutant exhibits a PDR phenotype, including elevated resistance to the mutagen 4-nitroquinoline-N-oxide, a known substrate for Snq2 but not for Pdr5 [17].
• In addition, we show that in the presence of cycloheximide or diazaborine PDR5 can be activated by additional transcription factors beside Pdr1p and Pdr3p [18].
• Analysis of the PDR1 deduced amino acid sequence revealed several homologies to four different regulatory proteins involved in the control of gene expression, including a cysteine-rich motif suggested to be a metal-binding domain for DNA recognition [19].
• YAP1 encodes a positive regulator with a leucine zipper motif that causes pleiotropic drug resistance when overproduced [11].

Physical interactions of PDR1

• Transcriptional activation by a GAL4p DNA binding domain fusion of PDR1p was enhanced in ngg1 and ada2 disruption strains [20].
• The putative consensus Yrr1p binding site deduced from these experiments, (T/A)CCG(C/T)(G/T)(G/T)(A/T)(A/T), is strikingly similar to the PDR element binding site sequence recognized by Pdr1p and Pdr3p [21].
• In addition, in vitro band shift assays demonstrate that a GST-Pdr1 fusion protein can bind to the PDREs of PDR10 and PDR15 [22].
• We show here that the RPN4 gene promoter contains regulatory sequences that bind Pdr1p and Pdr3p, two homologous zinc finger-containing transcription factors, which mediate multiple drug resistance through the expression of membrane transporter proteins [23].
• In this study, we have found that there are three sites in the PDR5 5'-noncoding region that are closely related to one another and are bound by both Pdr1p and Pdr3p [24].

Regulatory relationships of PDR1

• Transcriptional activation by yeast PDR1p is inhibited by its association with NGG1p/ADA3p [20].
• These pleiotropic drug resistance loci are under the control of the key transcription factors Pdr1p and Pdr3p [25].
• We also demonstrated that expression of RSB1 is under the control of the transcriptional factor Pdr1p [26].

Other interactions of PDR1

• Expression of these genes is under the control of two homologous zinc finger-containing transcription regulators, Pdr1p and Pdr3p [27].
• The PDR1 T879M mutant increased PDR5 transcription compared with wild-type PDR1 strains [1].
• Amino acids 274-307 of NGG1p were required for interaction with PDR1p [20].
• Similar to its action on GAL4p, the ADA complex acts to inhibit the activation domain of PDR1p [20].
• The ATP-binding cassette multidrug transporter Snq2 of Saccharomyces cerevisiae: a novel target for the transcription factors Pdr1 and Pdr3 [17].

Analytical, diagnostic and therapeutic context of PDR1

• Functional dissection of Pdr1p, a regulator of multidrug resistance in Saccharomyces cerevisiae [25].
• Genetic and Western blotting experiments indicated that Pdr13p exerts its effect on Pdr1p at a posttranslational step [9].
• We found that the regulation of these four genes depends on Pdr1p, since promoter activities studied by lacZ fusion analysis and mRNA levels studied by Northern blotting analysis changed upon deletion or hyperactivation by the pdr1-3 mutant of this transcription factor [28].
• To identify novel targets of Pdr1p, we compared transcriptomes among the yeast cells bearing wild, disrupted and gain-of-function alleles of PDR1 using a high-throughput fluorescent differential display PCR [29].
• Active efflux by multidrug transporters as one of the strategies to evade chemotherapy and novel practical implications of yeast pleiotropic drug resistance [30].

References